Hyperplasia is a general medical term referring to excess cell proliferation and benign prostatic hyperplasia is non-malignant enlargement of the prostate gland caused by increase in the number of stromal and epithelial cells resulting in obstruction of the proximal urethra, thus causes urinary flow disturbances [Roehrborn, C. G. BJU Int. 2006, 97, 7; Emberton, M. BJU Int. 2006, 97, 12 and Fitzpatrick, J. M. BJU Int. 2006, 97, 3]. It is leading disorder of the elderly male population and prevalence increases with age affecting around 80% by the age of 80 years. Nearly all men will develop microscopic BPH (Benign Prostatic Hyperplasia) by the age of 90 [Berry, S. J. et. al., Br. J. Urol., 1995, 5, 85].
Number of different causes for the overgrowth includes age, late activation of cell growth, abnormal increase in the clonal expansion of transit cell and change in ratios of androgen-estrogen level, which promote growth of prostatic tissue [Theomher, M. et al. Prostate, 1996, 28, 392 and Jenkins, E. P et al. J. Clin. Invest., 1992, 89, 293]. But the most widely accepted hypothesis is the dihydrotestosterone hypothesis which postulates that BPH occurs following an age related changes in the prostate androgen metabolism which favours accumulation of dihydrotestosterone.
Dihydrotestosterone (DHT), the most potent circulating androgen hormone, is produced by NADPH dependent stereoselective reduction of testosterone (T), under catalysis of the enzyme steroid 5α-reductase (5AR) as shown in FIG. 1 and FIG. 2 [Hitoshi, T. et al. Chem. Pharm. Bull., 2000, 48, 552]. Within prostate dihydrotestosterone binds to cytosol androgen receptor protein (AR) and DHT-AR complex enters the nucleus, interacts with DNA binding sites where it stimulates the RNA synthesis (FIG. 1) [Liao, S. Int. Rev. Cytol. 1975, 41, 87]. The concentration of dihydrotestosterone is 2.5 fold higher than in normal prostate.
Therefore, inhibition of androgen action by 5α-reductase is a logical treatment of 5α-reductase activity disorder i.e. benign prostatic hyperplasia.
Androgen suppression causes reduction in prostatic volume which is believed to decrease the static component of bladder outlet obstruction resulting from benign prostatic hyperplasia (FIG. 2) [Reid, P. et al. J. Clin Invest. New Drugs. 1999, 17, 271]. With the discovery of two 5α-reductase isozymes, their physiological and pharmacological roles in BPH, a significant research has been carried out to synthesize and evaluate nonsteroidal [Marisa, C. et al. Chem. Pharm. Bull., 2001, 49, 525, Frye, J. Med. Chem., 1994, 37, 2352] and steroidal compounds [Leny, M. A. et al. J. Steroid Biochem. Mol. Biol., 1994, 48, 197, Toshiaki, K. et al., Chem. Pharm. Bull., 1996, 44, 115] as competitive [4-azasteroids, 6-azasteroids] or non-competitive [3-carboxysteroids] inhibitors of 5α-reductase. Of these, only Finasteride (3) (MK-906) [Foley, C. L. et al. Drugs of Today 2004, 40, 213], and Dutasteride (4) [Susumu, T.; et al. Chem. Pharm. Bull., 2000, 48, 1689] are being used clinically in the treatment of benign prostatic hyperplasia.
It has been reported that various steroidal compounds possess high affinity for 5α-reductase inhibitors on account of their ability to form a coordinate bond with iron heame [Hartmann, R. W. et al.; J. J. Med. Chem. 2000, 43, 4266]. On other hand, progesterone esters (5,6) synthesised by Mexico laboratory exhibited high antiandrogenic activity [Cabeza, M. et al.; Chem. Pharm. Bull. (Tokyo) 1999, 47, 1232 and Cabeza, M. et al. Chem. Pharm. Bull. (Tokyo) 2001, 49, 1081.
On long term usage of Finasteride and Dutasteride the most common reported side effect include decreased libido, decreased ejaculate amount and erectile dysfunction. Whereas progesterone esters have been found to possess good antiandrogenic activity but are still under clinical investigation.
Based on these observations, it was envisaged to synthesize 17-oximino-5-androsten-3β-yl esters (10-16). Benign prostatic hyperplasia is also described by abnormal increase in the number of cells in prostate which may result not only from increased cell proliferation but also from decreased level in programmed cell death (apoptosis). These analogues were evaluated for 5α-reductase inhibitory activity and antiproliferative activity. These compounds may be useful in androgen dependent benign prostatic hyperplasia, by acting not only at the molecular level for the underlying cause of the disease but also decreasing the growth of prostate by killing cells.